Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease

Lickteig, Andrew J.; Fisher, Craig D.; Augustine, Lisa M.; Aleksunes, Lauren M.; Besselsen, David G.; Slitt, Angela L.; Manautou, José E.; Cherrington, Nathan J.

doi:10.1124/dmd.107.015107

Cited by 83 publications

(103 citation statements)

References 59 publications

(64 reference statements)

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“…Abcc3 and 4 are basolateral efflux transporters that pump various endogenous and exogenous chemicals from hepatocytes to blood; multiple drug and drug metabolites have been identified as substrates for human and mouse ABCC3/Abcc3 and ABCC4/Abcc4 (Kruh and Belinsky, 2003). Induction of Abcc3 and Abcc4 by chemical inducers or nonalcoholic steatohepatitis is associated with altered vectorial excretion of acetaminophen glucuronide (Lickteig et al, 2007a). In contrast with Abcc3 and 4, Abcc1 mRNA expression was decreased in livers of DIO mice.…”

Section: Discussionmentioning

confidence: 98%

“…Given the increased number of persons presenting with NAFLD and NASH and emerging evidence that fatty liver affects transporter expression in humans and rodents (Lickteig et al, 2007a), there is a growing need to better predict drug absorption, distribution, metabolism, and elimination, efficacy, and drug-induced liver injury using rodent models of obesity and diabetes.…”

Section: More and Slittmentioning

confidence: 99%

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Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

Slitt

2011

Drug Metab Dispos

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ABSTRACT:Drug pharmacokinetics can be altered in obese and diabetic subjects. In consideration of the prevalence of obesity and diabetes, characterization of transporter expression in mouse models of diabetes and obesity may be a useful tool to aid in prediction of altered drug pharmacokinetics or adverse drug reactions. It has been reported that ob/ob mice, which display a severe obesity and diabetes phenotype, exhibit multiple changes in drug transporter expression in liver and kidney. In the present study, the mRNA and protein expression of major drug transporters was determined in livers and kidneys of diet-induced obese (DIO) C57BL/6J male mice. The mice were fed a high-fat diet (HFD) (60% fat) from 6 weeks of age and display obesity, fatty liver, and mild hyperglycemia. The HFD diet increased expression of multidrug resistanceassociated proteins Abcc3 and 4 mRNA and protein in liver by 3.4-and 1.4-fold, respectively, compared with that detected in control mice fed a low-fat diet (LFD). In contrast, Abcc1 mRNA and protein decreased by 50% in livers of DIO mice compared with those in livers to lean mice. The HFD did not alter transporter expression in kidney compared with the LFD. In summary, unlike ob/ob and db/db mice, DIO mice exhibited a selective induction of efflux transporter expression in liver (i.e., Abcc3 and 4). In addition, dietinduced obesity affects transporter expression in liver but not kidney in the C57BL/6J mouse model. These data indicate that hepatic transporter expression is only slightly altered in a model of mild diabetes and nonalcoholic fatty liver disease and obesity.

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Section: Discussionmentioning

confidence: 98%

Section: More and Slittmentioning

confidence: 99%

Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

Slitt

2011

Drug Metab Dispos

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“…For example, the expressions of the bile salt export pump, MRP2, and OATP(s) were all reported to be decreased after 24 h of reperfusion in rats, while multidrug resistance protein 1B was increased. [22][23][24] In nonalcoholic fatty liver disease, expression of MRP2 has been reported to be upregulated, 41 whereas it was relatively well preserved in cholestasis and primary biliary cirrhosis. 42,43 Interestingly, mRNA and protein levels of the OATP2 transporter appeared contradictory after 4 h of reperfusion [ Fig.…”

Section: Discussionmentioning

confidence: 99%

Intravital multiphoton microscopy can model uptake and excretion of fluorescein in hepatic ischemia-reperfusion injury

et al. 2013

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Abstract. The liver is important in the biotransformation of various drugs, where hepatic transporters facilitate uptake and excretion. Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery, and the developing oxidative stress can lead to graft failure. We used intravital multiphoton tomography, with fluorescence lifetime imaging, to characterize metabolic damage associated with hepatic I/R injury and to model the distribution of fluorescein as a measure of liver function. In addition to measuring a significant increase in serum alanine transaminase levels, characteristic of hepatic I/R injury, a decrease in the averaged weighted lifetime of reduced nicotinamide adenine dinucleotide phosphate was observed, which can be attributed to a changed metabolic redox state of the hepatocytes. I/R injury was associated with delayed uptake and excretion of fluorescein and elevated area-under-the-curve within the hepatocytes compared to sham (i.e., untreated control) as visualized and modeled using images recorded by intravital multiphoton tomography. High-performance liquid chromatography analysis showed no differences in plasma or bile concentrations of fluorescein. Finally, altered fluorescein distribution was associated with acute changes in the expression of liver transport proteins. In summary, multiphoton intravital imaging is an effective approach to measure liver function and is more sensitive in contrasting the impact of I/R injury than measuring plasma and bile concentrations of fluorescein.

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“…The efficacy and toxicity of drugs targeting the central nervous system are largely deter-mined by the function and expression of these transporters and by their selectivity and affinity toward the substrates [6,7] . Several studies have verified that the functions of P-gp and Mrp2 at BBB are affected by various disease states, including diabetes mellitus [8,9] , acute myeloid leukemia [10] , cancer [11] and liver failure [12][13][14] . Our previous studies have also demonstrated that both the function and expression of P-gp and Mrp2 are markedly altered in brain tissues in thioacetamide/ hyperammonemia-induced liver dysfunction rodent models [15,16] .…”

Section: Introductionmentioning

confidence: 99%

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

Ling

Zhang

et al. 2016

Acta Pharmacol Sin

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Aim: Liver failure is associated with dyshomeostasis of efflux transporters at the blood-brain barrier (BBB), which contributes to hepatic encephalopathy. In this study we examined whether breast cancer resistance protein (BCRP), a major efflux transporter at the BBB, was altered during liver failure in rats. Methods: Rats underwent bile duct ligation (BDL) surgery, and then were sacrificed after intravenous injection of prazosin on d3, d7 and d14. The brains and blood samples were collected. BCRP function at the BBB was assessed by the brain-to-plasma prazosin concentration ratio; Evans Blue extravasation in the brain tissues was used as an indicator of BBB integrity. The protein levels of BCRP in the brain tissues were detected. Human cerebral microvessel endothelial cells (HCMEC/D3) and Madin-Darby canine kidney cells expressing human BCRP (MDCK-BCRP) were tested in vitro. In addition, hyperbilirubinemia (HB) was induced in rats by intravenous injection of unconjugated bilirubin (UCB). Results: BDL rats exhibited progressive decline of liver function and HB from d3 to d14. In the brain tissues of BDL rats, both the function and protein levels of BCRP were progressively decreased, whereas the BBB integrity was intact. Furthermore, BDL rat serum significantly decreased BCRP function and protein levels in HCMEC/D3 cells. Among the abnormally altered components in BDL rat serum tested, UCB (10, 25 µmol/L) dose-dependently inhibit BCRP function and protein levels in HCMEC/D3 cells, whereas 3 bile acids (CDCA, UDCA and DCA) had no effect. Similar results were obtained in MDCK-BCRP cells and in the brains of HB rats. Correlation analysis revealed that UCB levels were negatively correlated with BCRP expression in the brain tissues of BDL rats and HB rats as well as in two types of cells tested in vitro. Conclusion: UCB elevation in BDL rats impairs the function and expression of BCRP at the BBB, thus contributing to hepatic encephalopathy.

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Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease

Cited by 83 publications

References 59 publications

Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

Intravital multiphoton microscopy can model uptake and excretion of fluorescein in hepatic ischemia-reperfusion injury

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

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